Genetic Variant SCARF2:p.Cys258Tyr (chr22-20431099-C-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_182895.5(SCARF2):c.773G>A(p.Cys258Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SCARF2
NM_182895.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.64

Publications

8 publications found

Variant links:

Genes affected

SCARF2 (HGNC:19869): (scavenger receptor class F member 2) The protein encoded by this gene is similar to SCARF1/SREC-I, a scavenger receptor protein that mediates the binding and degradation of acetylated low density lipoprotein (Ac-LDL). This protein has only little activity of internalizing modified low density lipoproteins (LDL), but it can interact with SCARF1 through its extracellular domain. The association of this protein with SCARF1 is suppressed by the presence of scavenger ligands. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

SCARF2 Gene-Disease associations (from GenCC):

van den Ende-Gupta syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia

SCARF2 links:

ENSG00000277971 (HGNC:):

ENSG00000277971 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.945

PP5

Variant 22-20431099-C-T is Pathogenic according to our data. Variant chr22-20431099-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 31046.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182895.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCARF2	NM_182895.5	MANE Select	c.773G>A	p.Cys258Tyr	missense	Exon 4 of 11	NP_878315.2	Q96GP6-2
	SCARF2	NM_153334.7		c.773G>A	p.Cys258Tyr	missense	Exon 4 of 11	NP_699165.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCARF2	ENST00000622235.5	TSL:1 MANE Select	c.773G>A	p.Cys258Tyr	missense	Exon 4 of 11	ENSP00000477564.2	Q96GP6-2
SCARF2	ENST00000623402.1	TSL:1	c.773G>A	p.Cys258Tyr	missense	Exon 4 of 11	ENSP00000485276.1	Q96GP6-1
ENSG00000277971	ENST00000429594.1	TSL:5	n.178-542G>A		intron	N/A	ENSP00000392268.1	H7BZZ5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1399594

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

691940

African (AFR)

AF:

0.00

AC:

AN:

32194

American (AMR)

AF:

0.00

AC:

AN:

38426

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25150

East Asian (EAS)

AF:

0.00

AC:

AN:

36832

South Asian (SAS)

AF:

0.00

AC:

AN:

80708

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5502

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1088084

Other (OTH)

AF:

0.00

AC:

AN:

58304

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Van den Ende-Gupta syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.78

MutationAssessor

Pathogenic

4.6

PhyloP100

7.6

PrimateAI

Pathogenic

0.92

Sift4G

Uncertain

0.013

Polyphen

1.0

Vest4

0.92

MutPred

0.75

Gain of phosphorylation at C258 (P = 0.0177)

MVP

0.42

ClinPred

1.0

GERP RS

4.2

Varity_R

0.74

gMVP

1.0

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over